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The anti-inflammatory agent colchicine is gaining interest as a treatment for coronary artery disease. However, the effects of colchicine in atherosclerotic animal models are mostly unknown. This study aimed to evaluate colchicine in a rabbit model of atherosclerosis.

ABSTRACTEvidence has demonstrated that miRNAs play an irreplaceable role in tumorigenesis and progression of a broad range of cancers, including gastric cancer. Among these miRNAs, miR-10a and miR-10b have been identified to critically participate in gastric carcinogenesis and malignant progression. In this review, we briefly describe the role of miR-10a and miR-10b in gastric cancer, especially in the regulation of cell proliferation, apoptosis, cell cycle, migration, invasion and metastasis, drug resistance, and cancer stem cells. Furthermore, we highlight several compounds that target the miR-10 family and exhibit antitumor activity in cancer cells. Moreover, we conclude that targeting the miR-10 family might be a promising approach for the treatment of gastric cancer.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2006.01.015 Byline: Yanfen Shi (c), Andre Y. Denault (a), Pierre Couture (a), Ady Butnaru (c), Michel Carrier (b), Jean-Claude Tardif (c) Abbreviations: A, atrial filling A-wave velocity; Am, late mitral annular velocity; Ar, reversed atrial flow; At, atrial filling tricuspid annular velocity; CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; D, diastolic D-wave velocity; DT, E-wave deceleration time; E, early mitral filling E-wave velocity; Em, early mitral annular velocity; Et, early filling tricuspid annular velocity; HVF, hepatic venous flow; IVRT, isovolumic relaxation time; LVDD, left ventricular diastolic dysfunction; LVEF, left ventricular ejection fraction; PVF, pulmonary venous flow; PW, pulsed wave; RVDD, right ventricular diastolic dysfunction; S, systolic S-wave velocity; TDI, tissue Doppler imaging; TMF, transmitral flow; TTF, transtricuspid flow; Vp, propagation velocity Abstract: We sought to study the evolution of biventricular filling properties after coronary artery bypass grafting. Author Affiliation: (a) Department of Anesthesia, Montreal Heart Institute, and University of Montreal, Montreal, Quebec, Canada (b) Department of Surgery, Montreal Heart Institute, and University of Montreal, Montreal, Quebec, Canada (c) Department of Medicine, Montreal Heart Institute, and University of Montreal, Montreal, Quebec, Canada Article History: Received 27 September 2005; Revised 10 January 2006; Accepted 13 January 2006 Article Note: (footnote) Supported by the Montreal Heart Institute Foundation and by the 2001 Dr Earl Wynands Research Award in Cardiovascular Anesthesia.

Inhaled milrinone (iMil) has been used for the treatment of pulmonary hypertension (PH) but its efficacy, safety, and prophylactic effects in facilitating separation from cardiopulmonary bypass (CPB) and preventing right ventricular (RV) dysfunction have not yet been evaluated in a clinical trial. The purpose of this study was to investigate if iMil administered before CPB would be superior to placebo in facilitating separation from CPB. High-risk cardiac surgical patients with PH were randomized to receive iMil or placebo after the induction of anesthesia and before CPB. Hemodynamic parameters and RV function were evaluated by means of pulmonary artery catheterization and transesophageal echocardiography. The groups were compared for the primary outcome of the level of difficulty in weaning from CPB. Among the secondary outcomes examined were the reduction in the severity of PH, the incidence of RV failure, and mortality. Of the 124 patients randomized, the mean (standard deviation [SD]) EuroSCORE II was 8.0 (2.6), and the baseline mean (SD) systolic pulmonary artery pressure (SPAP) was 53 (9) mmHg. The use of iMil was associated with increases in cardiac output (P= 0.03) and a reduction in SPAP (P= 0.04) with no systemic hypotension. Nevertheless, there was no difference in the combined incidence of difficult or complex separation from CPB between the iMil and control groups (30% vs28%, respectively; absolute difference, 2%; 95% confidence interval [CI], −14 to 18; P= 0.78). There was also no difference in RV failure between the iMil and control groups (15% vs14%, respectively; difference, 1%; 95% CI, −13 to 12; P= 0.94). Mortality was increased in patients with RV failure vsthose without (22% vs2%, respectively; P< 0.001). In high-risk cardiac surgery patients with PH, the prophylactic use of iMil was associated with favourable hemodynamic effects that did not translate into improvement of clinically relevant endpoints. This trial was registered at ClinicalTrials.gov; identifier: NCT00819377. La milrinone inhalée est utilisée pour traiter l’hypertension pulmonaire (HP) mais son efficacité, son innocuité et ses effets prophylactiques pour faciliter le sevrage de la circulation extracorporelle (CEC) et prévenir la dysfonction ventriculaire droite (VD) n’ont pas encore été évalués dans le cadre d’une étude clinique. L’objectif de cette étude était d’examiner si la milrinone inhalée avant la CEC serait supérieure à un placebo pour faciliter le sevrage de la CEC. Des patients de chirurgie cardiaque à risque élevé et souffrant d’HP ont été randomisés à recevoir de la milrinone inhalée ou un placebo après l’induction de l’anesthésie et avant la CEC. Les paramètres hémodynamiques et la fonction VD ont été évalués à l’aide d’un cathéter de l’artère pulmonaire et d’une échocardiographie transœsophagienne. Les groupes ont été comparés selon notre critère d’évaluation principal, soit le niveau de difficulté du sevrage de la CEC. Parmi les critères d’évaluation secondaires examinés figuraient la réduction de la gravité de l’HP, l’incidence d’insuffisance cardiaque droite et la mortalité. Au total, 124 patients ont été randomisés. Le score EuroSCORE II moyen (écart type [ÉT]) était de 8,0 (2,6), et la pression systolique de l’artère pulmonaire moyenne de base (ÉT) était de 53 (9) mmHg. L’utilisation de milrinone inhalée a été associée à des augmentations du débit cardiaque (P= 0,03) et à une réduction de la pression systolique de l’artère pulmonaire (P= 0,04) sans hypotension systémique. Toutefois, aucune différence n’a été observée dans l’incidence combinée de sevrage difficile ou complexe de la CEC entre le groupe milrinone inhalée et le groupe témoin (30 % vs28 %, respectivement; différence absolue, 2 %; intervalle de confiance [IC] 95 %, −14 à 18; P= 0,78). Aucune différence n’a été observée non plus en matière d’insuffisance cardiaque droite entre le groupe milrinone inhalée et le groupe témoin (15 % vs14 %, respectivement; différence, 1 %; IC 95 %, −13 à 12; P= 0,94). La mortalité était augmentée chez les patients avec insuffisance cardiaque droite (22 % vs2 %, respectivement; P< 0.001). Chez les patients de chirurgie cardiaque à risque élevé atteints de HP, l’utilisation prophylactique de milrinone inhalée a été associée à des effets hémodynamiques favorables qui ne se sont pas traduits en améliorations des critères pertinents d’un point de vue clinique. Cette étude a été enregistrée au ClinicalTrials.gov; identifiant : NCT00819377.

Polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the benefits of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on cardiovascular events after acute coronary syndrome. We hypothesized that Adcy9inactivation could improve cardiac function and remodeling following myocardial infarction (MI) in absence of CETP activity.

Background: Amiodarone is commonly used in the acute care setting. However the acute hemodynamic and echocardiographic effect of intravenous amiodarone administered intraoperatively on right ventricular (RV) systolic and diastolic function using transesophageal echocardiography (TEE) has not been described.Methods: The study design was a randomized controlled trial in elective cardiac surgical patients undergoing valvular surgery. Patients received an intravenous loading dose of 300 mg of either amiodarone or placebo in the operating room, followed by an infusion of 15 mg/kg for two days. Hemodynamic profiles, echocardiographic measurement of RV and left ventricular (LV) dimensions, Doppler interrogation of tricuspid and mitral valve, hepatic and pulmonary venous flow combined with tissue Doppler imaging of the tricuspid and mitral valve annulus were obtained before and after bolus.Results: Although more patients in the placebo group had chronic obstructive lung disease (14 vs 6, p=0.05) and diabetes (14 vs 5; p=0.0244), there was no difference in terms of baseline hemodynamic, 2D and Doppler variables. After bolus, a significant increase in pulmonary artery pressure, central venous pressure and pulmonary vascular resistance index (p<0.05) was observed in the amiodarone group with reduction in systolic to diastolic (S/D) ratio of the hepatic (p=0.0247) and pulmonary venous (p=0.0052) velocity.Conclusion: Acute administration of amiodarone is associated with alteration in RV diastolic properties and has minimal negative inotropic effect on RV systolic function in cardiac surgical patients with valvular disease.

Introduction:Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. Chlordecone (CLD) is a pesticide known for its carcinogenic effects. Data suggest that CLD may disrupt the activity of myocardial Na+/K+-ATPase, deregulate mitochondrial Mg2+/ATPase in cardiomyocytes (CM), and inhibit CM Ca2+/ATPase. Little is known about the link between CLD and AF.Hypothesises:1. Prolonged exposure to CLD induces arrhythmogenic cardiac remodeling in rats. 2.Cycle of CLD-withdrawal is accompanied by reduction of CLD-induced AF vulnerability.Methods:Male Wistar rats (250g) were exposed to CLD (0.1 μg/L or 1 μg/L) diluted in their daily water for 28 days. Control rats (CTRL) received water without CLD. Starting on day 29, all animals were exposed to CLD-free water. Electrophysiological study (EPS), echocardiography, and cardiac optical mapping (OM) were performed at days 28 and 56 to study cardiac function and atrial conduction. Expression levels of genes and proteins involved in inflammation, fibrosis and senescence were quantified by histology, immunoblot and qPCR.Results:At D28, all CLD-rats developed AF while CTRL rats did not. Compared to CTRL, weight up-take and water consumption were lower in animals exposed to CLD, although their food consumption was higher. Echocardiography revealed that CLD animals showed increased left ventricular contractility and atrial filling compared to CTRL. Acute CLD contamination caused a decrease in atrial conduction velocity and atrial action potential durations determined by cardiac OM ex-vivo. A 28-days CLD-withdrawal cycle was accompanied by weight normalization, and attenuation of AF inducibility, without improving atrial fibrosis and AF duration. CLD also decreased right and left atrial p21 mRNA expression, an effect not reversed by CLD weaning.Conclusion:CLD exposure is associated with increased AF vulnerability. CLD-weaning decreased (without abolishing), cardiac fibrosis and AF susceptibility.

Diastolic dysfunction often precedes the onset of diastolic heart failure. We previously demonstrated that diastolic dysfunction and left ventricular hypertrophy (LVH) in Dahl salt-sensitive rats can be ameliorated by quantitative trait loci (QTLs).

Diastolic dysfunction often represents the onset of diastolic heart failure (DHF). We previously showed in principle that diastolic function in Dahl salt-sensitive rats (DSS) can be genetically determined by quantitative trait loci (QTLs) that also modulate blood pressure (BP).

Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation. The present study examined the potential role of miR-21 in the atrial AF substrate resulting from experimental heart failure after myocardial infarction (MI).

By using water-soluble linear phenolic resin (PF) as C-source, a graphite-like carbonaceous surface modified TiO2photocatalyst (PF/TiO2) was successfully synthesized through a hydrothermal process. The as-formed PF/TiO2exhibited significantly higher photocatalytic activity than bare TiO2toward the degradation of methyl orange (MO) under visible irradiation, while a tetrahydrofuran (THF) postrinsing operation can further enhance the photocatalytic activity of PF/TiO2. To exploit the mystery of surface carbonaceous covering, a series of characterizations such as XPS, TG, TEM, and FTIR, as well as 1H NMR were employed. It is proposed that PF experienced a cross-linking and a carbonization process that are catalyzed by TiO2at the surface of TiO2. The as-formed organics covering on the PF/TiO2seems composed of four portions from the surface of TiO2to the outside as oxidized graphite-like carbon (OGC), graphite-like carbon (GC), cross-linked PF (cl-PF), and PF. OGC and GC substances endow the catalysts visible absorption and photocatalytic activity, which are insoluble in the THF; meanwhile, PF and cl-PF are adverse to the visible light photocatalysis and can be rinsed out with THF. The visible light photocatalytic activity unrinsed PF/TiO2reaches its optimal condition at a PF dosage of 0.7 g (for 5.0 g titanium sulfate) while the THF rinsed PF/TiO2presents the highest photocatalytic activity with the maximum PF dosage in this work and gives a MO degradation rate of 100% in 4 h.

Atrial fibrillation impairs atrial contractility, inducing atrial stunning that promotes thromboembolic stroke. Action potential AP-prolonging drugs are reported to normalize atrial hypocontractility caused by atrial tachycardia remodeling ATR. Here, we addressed the role of AP duration APD changes in ATR-induced hypocontractility.

Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload. Furthermore, we showed that argonaute 2 (AGO2), a key component of the RNA-induced silencing complex, was a substrate of PTP1B in cardiomyocytes and in the heart. Our results revealed that phosphorylation at Tyr393and inactivation of AGO2 in PTP1B cKO mice prevented miR-208b–mediated repression of thyroid hormone receptor–associated protein 1 (THRAP1; also known as MED13) and contributed to thyroid hormone–mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3) with propylthiouracil rescued pressure overload–induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity is cardioprotective and that redox signaling is linked to thyroid hormone responsiveness and microRNA-mediated gene silencing in pathological hypertrophy.

Hypertension and diastolic heart failure are two common cardiovascular diseases that inflict heavy morbidity and mortality, yet relatively little is understood about their pathophysiology. The identification of quantitative trait loci for blood pressure is important in unveiling the causes of polygenic hypertension. Although Dahl salt-sensitive strain is also an excellent model for the study of diastolic heart failure, virtually nothing is known about the quantitative trait loci determining diastolic heart failure. Diastolic dysfunction often represents the onset of diastolic heart failure.

Ovarian cancer (OC) is the most aggressive gynecological cancer. Even with the advances in detection and therapeutics, it still remains clinically challenging and there is a pressing need to identify novel therapeutic strategies. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in OC. In this study, we found the MTDH is overexpressed in OC tissues. Through in vitro assays with overexpression cells, we characterized the role of MTDH. We confirmed MTDH stable overexpression significantly increased the expression of TNF-α, IL-6, IL-8, IL-10, and IL-1β. Interestingly, NF-kappa-B (NF-κB) and MTDH were found in a feed-forward loop motif. Thus, our findings support the notion that the MTDH and NF-κB signaling network contributes to OC traits. MTDH represents a new OC-associated gene that can contribute to insights of OC biology and suggests other treatment strategies.

Pharmacogenomic studies have shown that polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the effects of dalcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, on cardiovascular events after an acute coronary syndrome. We hypothesized that Adcy9inactivation could improve cardiac function and remodeling after myocardial infarction (MI) in the absence of CETP activity.Wild-type (WT) and Adcy9-inactivated (Adcy9Gt) mice, transgenic (tg) or not for human CETP, were subjected to MI by permanent left anterior descending coronary artery ligation (n=22-24/genotype) and studied for 4 weeks. There was no significant difference between groups in cardiac troponin I in serum and left ventricular (LV) wall motion score index (WMSI) on echocardiography at 24 hours post-MI. Mice with insufficient myocardial damage (WMSI?1.2) at 24 hours were excluded. The total mortality rate was 45%, without difference between genotypes (p=0.98), which resulted in 11 mice with each genotype (n=44) undergoing echocardiography at baseline, weeks 1 and 4 post-MI. All of these mice developed LV hypertrophy, dilation and systolic dysfunction over time, but Adcy9Gtmice exhibited reduced pathological LV remodeling and better LV function compared to WT after MI (p<0.05, Table). Histology analyses performed at 4-week follow-up indicated smaller cardiomyocyte size (p<0.01) and reduced infarct size (p=0.07) in Adcy9Gtversus WT mice. There were no significant differences between CETPtg and Adcy9Gt-CETPtg mice, which both exhibited intermediate responses compared to those of WT and Adcy9Gtmice.In conclusion, Adcy9inactivation reduces pathological LV remodeling and improves cardiac function after MI, but only in the absence of CETP activity.

Pulmonary hypertension (PH) associated with left heart disease, or group II PH, is the most prevalent type of PH. Although it carries worse outcomes mainly due to the development of right ventricular failure, its biology remains to be fully elucidated and there is currently no therapy specifically approved for prevention or treatment of group II PH. Here, we aim at characterizing the transcriptomic effects of a new drug modulating fatty acid receptors, PBI-4050, in the lungs at recovery from large myocardial infarction (MI) causing PH. PBI-4050, valsartan or the combination were administered starting 48hr after MI for a duration of 5 weeks. We performed differential gene expression analysis and identified co-expression networks using 72 RNAseq lung samples from male rats. We were able to reconstruct gene expression signatures at the isoforms levels. Differential gene expression was assessed using state of the art methods that take into account potential technical biases. Gene co-expression networks were analysed through computational genomics approaches and lead to a better understanding of differentiated pathways. Our findings reveal that a combination of the new drug PBI-4050 with the angiotensin II receptor antagonist valsartan is highly beneficial in this group II PH model, and the genetic and metabolic networks modulated by this treatment are identified (Figure 1). The combined transcriptomic benefit of these drugs mirrored the biologic effects as only combination therapy improved right ventricular hypertrophy and function. We also analyzed the effects of large MI on the lung transcriptome prior to treatment, revealing new insights into PH disease etiology. In conclusion, we showed that, after large MI causing PH, PBI-4050 therapy provides added benefit to valsartan, by positive lung transcriptomic remodeling improving RV function and hypertrophy. Finally, trancriptomics analyses may allow the identification of novel therapeutic pathways.

Objectives: Atrial tachycardia-induced remodeling (ATR) and ventricular tachypacing-induced heart failure (HF) create experimental substrates for atrial fibrillation (AF), and both have been reported to produce atrial dilation and hypocontractility. The relative importance of changes in atrial size and contractility in the two models is unknown. This study compared changes in atrial dimensions and emptying in ATR versus HF dog models and related them to AF promotion. Methods: In ATR dogs (n=11), the right atrium (RA) was paced at 400/min for 42 days. In HF dogs (n=10), the right ventricle was paced at 240 bpm for 2 weeks, followed by 3 weeks at 220 bpm. Transthoracic echocardiography was performed at baseline and weekly thereafter. At a terminal electrophysiological study, RA effective refractory period (ERP) was recorded and AF induced repeatedly by atrial burst pacing to measure mean AF duration (DAF). Results: Left atrial (LA) systolic area increased by 10.0% in ATR versus 48.2% in HF dogs (P=0.008), with significant time-dependent changes in HF (P=0.0001), but not ATR (P=0.16). LA diastolic area increased over time in both groups (P=0.004, 0.0001 for ATR and HF respectively), but increases were much larger in CHF (80.2%) compared to ATR (24.2%, P=0.0002). Similar findings were obtained for RA. Fractional area shortening (FAS) decreased by 19.4% (ATR) versus 41.8% (HF, P=0.007) in LA and 13.7% (ATR) versus 33.7% (HF, P=0.03) in RA. RA ERP correlated with DAF in ATR dogs (r=−0.79, P<0.001), but not in HF dogs (r=0.20, P=NS). DAF and diastolic areas of RA and LA were highly correlated (r=0.71, 0.77; P<0.01 for each) in HF dogs, but not in ATR dogs (r=−0.18, 0.29; P=NS). Conclusions: Remodeling of atrial size and emptying function is much greater in HF than in ATR. Whereas in ATR, electrophysiological remodeling is of prime importance in AF promotion, structural remodeling (as reflected in changes in atrial size and contraction) appears much more important in HF-induced AF.